Veterinary tetravalent tin compositions



United States VETERINARY TETRAVALENT TIN COMPOSITIONS Kathe] B. Kerr and Arthur W. Walde, Charles City, Iowa, assignors to Dr. Salsburys Laboratories, a corporation of Iowa No Drawing. Original application November 20, 1953,

Serial No. 393,498. Divided and this application ctober 11, 1954, Serial No. 461,672

19 Claims. (*Cl. 167---53) This invention relates to a new type of veterinary preparations adapted for use in the treatment of domesticated animals and fowl.

In its more specific aspects the invention pertains to novel preparations and treatments for the prevention and suppression of various pathological conditions which affeet the alimentary tract of domestic animals and poultry.

A further object of the invention is the formulation of medicated compositions for enhancing the meat producing capacity of marketable animals and sustaining all or at least part of the normal growth rate under diseased conditions.

The present application is a continuation-in-part of the subject matter of copending application Serial No. 200,310, filed December 11, 1950, now abandoned, and a division of the subject matter of copeuding application Serial No. 393,498, filed November 20, 1953.

Livestock and birds, as well as dogs, are subject to numerous diseases of highly contagious nature. Among those of economic importance for the poultry and livestock industry are various types of coccidiosis, hexamitiasis in turkeys and worm infections.

Coccidiosis in chickens ma be caused by different etiological factors among v a Eimeria tenella and Eimeria necatrix rank as the ost devastative species.

Eimeria tenella is a proto n and is responsible for the form of coccidiosis which generally known as the cecal type. The parasite is introduced into the intestinal tract in the form of encysted oospores or oocys'ts which are found in the droppings and in feed contaminated therewith. After invasion of the digestive system of the host the organism undergoes its natural life cycle, rapidly multiplies, and after release of the sporozoites erodes the epithelial tissue of the cecnm and small intestine thereby producing hemorrhage, unthriftiness, weakness, emaciation and death. Mortality due to cecal coccidiosis in chickens during the first month of life has been estimated at to 20 per cent. Older birds which do not succumb to the infection have inferior market value due to debilitation or they may be altogether unfit for consumption.

While Eimeria tenella is mainly localized in the cecal area, Eimeria necazrix, another protozoan parasite of the coccidial genus, attacks the small intestine involving the middle part of the canal. The pathological conditions developed by this infection may be either acute or chronic. In its acute form the disease may be fatal to the bird five or seven days after infection; the chronic type of the disorder leads to marasmus and progressive emaciation.

Coccidiosis in turkeys may be attributable to a number of coccidial species, such as Eimeria meleagridis, Eimeria meleagrimitis, Eimeria dispersa, Eimeria gallopavonis, Eimeria adenoeides, and Eimeria innocua. While each of these organisms has its own biological and pathogenic pattern and is therefore not necessarily amenable to the same type of chemotherapeutic treatment, the outward symptoms seen in the infections may present a similar picture. They are usually recognized in listlessness, huddling, cheeping and anorexia. Feed consumption decreases about the fourth day following infection with rapid loss of weight and death occurring between the fifth and seventh day. Hemorrhagic diarrhea is likewise observed. Poults under 12 weeks of age are the most vulnerable to the disease.

The principal region of Eimeria melengritlis invasion in adult turkeys is the ceca, while in iowe" of the small mi... 1

intestinal tract may be likewise attacked. The species of Eimeria meleagrz'mitis on the other hand colonizes the epithelium of the villi of the jejunum during development. Contrary to Eimeria meleagridis the schizonts of which parasitize the surface epithelium rather than the glandular parts, Eimeria meleagrimitis is deeply embedded in the epithelium below the nucleus.

Hexamitiasis, also known as infectious catarrhal enteritis, is a disease of young poults and presents a serious problem to the turkey industry. Highest mortality is encountered in birds under ten weeks of age. The causative agent of this infection has been recognized to be a member of the Hexamita genus, called Hexamita meleagrirlis. The organism is found in large numbers throughout the small intestine with fewer colonies localized in the ceca. It is a fiagellate protozoan and its high incidence in turkey flocks makes it the primary source of contamination. In the first stages of outbreak the pathological syndrome in cludes nervousness, subnormal body temperature, stilted gait, ruffled feathers and foamy, watery diarrhea. Despite continued undiminished feed consumption the birds lose weight because of digestive ditficulties and improper assimilation of the feed. The symptoms grow rapidly worse with listlessness, huddling and coma leading to death. The infection commonly reaches epidemic proportions with a high rate of mortality. In cases of milder and subacute attacks, progressive emaciation is the most prominent sign, and a large number of stunted birds destroy the value of the flock.

Fowl, livestock and other domestic animals are also frequently infected with worms among which the cestodes and nematodes are of chief concern to the veterinarian.

The habitat of cestodes, which are also known by term of tapeworms, is principally the small intestine of host. They form typical segments or proglottids which are mostly detectable when passed out in the droppings. The Worms have no digestive tract, and depend for their nutriment upon the direct contact of their body surface with the intestinal contents and the lining of the intestinal wall whereon they are anchored by two to four cup-like organs or suckers provided on the head or scolex of the parasite. Supplementary thereto, the scolices of the worms are sometimes equipped with hooks. It is these suckers and hooks which hold the worm in firm attachment to the intestinal wall of the animal and make its removal by chemical agents most dilficult. Furthermore the scoler: is the portion of the worm which proliferates the proglottids; therefore to completely expel the wor a it is necessary to remove the scolex.

Que of the most prevalent species of cestodes occurring in poultry is Raillietirza cestz'cillus, which invades the lower duodenal and jejunal regions of the infected bird. These parasites are transmitted to the fowl by an inter' mediate host, such as ground or dung beetles which in gest the worm in the form of its eggs or so-called oncospheres. These in turn develop into another larval stage or cysticercoid in the course of their life cycle. Poultry become infected with Raillietina ceszicillus by swallowing the intermediate hosts with food or water. After reach ing the intestinal tract, the cysticercoid is released from the body of the intermediate host by the action of di gestive juices; the inner surface of the larval head which is equivalent to the scolex of the adult worm pushes one ward and attaches itself to the intestinal wall. New seg ments start to form at the posterior or neck portion of the scolex, and within about three weeks develop into fully mature tapeworms. Raillietina cesticillus infec tions in poultry seriously impair the health and normal development of the birds. They may cause irritation and inflammation of the intestinal mucous membranes. As a consequence, growth rates are noticeably decreased, and

in more severe cases catarrhal enteritis, diarrhea and general debilitation may result.

Nematodes, or roundworms, are another important and injurious group of poultry parasites. Like the cestodes, some of the roundworm species are of the indirect type, and require an intermediate host for their propagation and dissemination. The more commonlv occurring species of nematodes have a direct type of life cycle requiring no intermediate host. in contrast to tapeworms, nematodes are provided with an alimentary pisiformis develops.

eyesore 3 tract. They are found in various locations of the avian body, but the gastrointestinal tract is the habitat of the largest number of roundworm species.

One of the most common nematode parasites of fowl lS Ascaridia gulli, which is a large, thick roundwormpf yellowish-white color. Infection results from swallow ng the infective eggs of the worm by the susceptible bird. The eggs hatch either in the duodenum or in the glandular stomach of the host, and the larvae thereupon penctrate the mucosa. As a result the afillcted chickens suffer from hemorrhage, glandular atrophy, retarded growth, and an increased susceptibility to other diseases. Drooplness, emaciation, and diarrhea are the visible clinical symptoms accompanying the penetration of the parasite.

In dogs, as in poultry, cestodes have an indirect type of life cycle, that is, an intermediate host is involved. prevalent species of tapeworm parasitizing the dog is Taem'a pisiformis. This is a large worm, usually seven inches or more in length. The intermediate host is the rabbit in which the cysticercus or larval stage of Titania The rabbit acquires its infection from eating food which has been contaminated with fecal material of infected dogs.

Dogs are likewise infected with nematode parasites. Three species are commonly found in the gastrointestinal tract, the dog ascarid Toxncara Curtis; the dog hookworm Ancylostoma canium; and the dog whipworm Trichuris vulpzs. Sheep and cattle are commonly infected with nematode and cestode parasites. Swine are almost universally infected with nematode parasites.

The control of the aforementioned intestinal infections is largely confined to prophylactic management and sanitary measures which are principally directed to the elimination of conditions favorable to the dissemination and transmission of the parasites. This involves not only the extensive removal of potential intermediate hosts and other sources of contamin in, but also the maintenance of an environment unsuitable for a possible development of the infective stages of the or Efiective sanitation necessarily also includes a and frequent disthe potentially infec and valuable these "lite limitations, both posal of the body wastes containin tive materials. However helpfn measures may be, they have the in respect to their efi'ectiveness an to the expenditure in labor, equipment and materials irred by these pro cedures. They require such elz crate and burdensome steps as brooding in special enclosures which have no co met with the soil, raising chickens and poults on perfectly clean ground isolated from other flocks. special equipment for feeding and Watering protected against fecal contami nation, and quarantining new stock for a prolonged period of time of observation to prevent immediate contact of the old flock with potental disease carriers of fresh arrivals.

Various chemotherapeutic agents have likewise been suggested for the control of the above listed diseases. Their administration in various forms, however, has not een successful for manifold reasons. Some of these substances lack in eificacy, while others are too toxic within the range of their therapeutic potency. Yet other remedies are of no practical value on account of their high cost of preparation. One of the main difiiculties in applying certain pharmaceutical compounds is their adverse effect upon the metabolic system of the animal at the required level of medication. This is evidenced by a decrease in food and water consumption, retardation of growth and maturity. and a decline of productivity. in respect to antheimintic preparations in particular, many of the suggested worm expellers are found to possess such high toxicity that they cannot be administered to the animal with any degree of safety. In order to be effective, the dosages to be given must be adequate to remove the worm; experience. however, shown that the same dosages of many or the commonly knov/r nts are likewise dangerous to the host. They may impcril the life of the animal itself, interfere with its normal development and growth, or weaken its productivity.

Another problem is the selection of the proper remedy which will act upon the specific parasite involved. This requires a positive id. "titration of the worm before treatment which is not a ys easy to establish. lvloreover, there is frequently occurring a 1. th roundworms and. tap

.115 which w rld single drug Rapidity in action and a high percentage of worm removal and disease survival are additional factors which determine the value of chemotherapeutic preparations. It might not always be possible to accomplish this result with one single material, especially in the case of a mixed infection with several worm species, but a favorable ratio of removal would be a considerable achievement in easing the load of parasites and checking the spread of pathological processes.

Finally, the choice of anthelmintics is often limited by numerous contraindications excluding a certain type of chemical compound which might be otherwise advisable. A calcium deficiency, for instance, would not permit the use of carbon tetrachloride. Other conditions which suggest caution in the use of worm expellants are great de bility, gastritis, and enteritis, as well as certain infectious diseases. Here again, however, the advisability of the type of vcrmifuge will greatly depend upon the necessary dosage of medication in relation to its toxicity to the host. Some of the known drugs have a low potency, and must be administered in substantial amounts for effective worrn removal. If the effective level of a material borders upon the threshold of toxicity, it is of questionable value, especially in the presence of other disorders. If, conversely, the level of elficacy lies far below the toxic range, the margin of safety is high; and the wider the span between incipient potency and toxic range, the broader the scope or applicability. It is precisely this latter type of drugs which are the most desirable for anthelmintlc therapy and other veterinary purposes and therefore eagerly sought for by the animal husbandryman.

One of the greatest shortcomings of the majority, if not all of the hitherto known veterinary remedies, consists in their high specificity to the causative organism. A medicament that is helpful in combatting Eimeria necatrix may have no effect in the control of cecal coccidiosis. Likewise a drug used in the control of hexamitiasis in turkeys will ordinarily be unavailable for the suppression of coccidiosis i the same avian species. Again neither one of these materials has any proven value as an anthelmlntic. Frequently, however, an animal is afilicted with more than one single infection at the same time, especially where the causative organism is carried into the system by a worm as an intermediate host. In such cases a fully expedient and adequate cure would require the concurrent administration of several specific drugs which are liable Z0 produce a cumulative toxic effect in the treated animal; or the chemotherapeutic result of these several ingredients so dispensed may altogether be nullified through mutual incompatibility and counteraction.

in the more restricted field of anthelmintics most of the previously em loyed remedies are limited in action in that they are specific to the type of the parasite, its habitat and host. Thus a variety of chemicals have been suggested for the elimination of worms. Thernajority of them have a distinct pharmacological function. Carbon tetrachloride, for instance, is effective against roundworms only, but must be administered at a rate of four to five cc. per kilogram body weight which may be injurious to animals in failing health. Chenopodium can be used only against nematodes and is not indicated in the presence of hepatic and gastrointestinal disorders. Phenothiazine is a specific vermicide for poultry and acts exclusively against Heterakis gallinae. It has a low margin of safety for swine. As for tapeworms, a large number of drugs have been proposed, but none has turned out to be entirely satisfactory. Kamala, which has been used for many years, seems to remove the chain of proglottids or strobiiae only, without affecting the head or scolex which rests attached to the intestine. Areca nut and its active constituent, the highly poisonous arecoline, is an effective cestodicidal drug for dogs, but its efiiciency in poultry has not been demonstrated.

Among the more recent developments in the field of anthelmintic therapy, various tin compounds have been investigated with inconsistent results. Some of these substances are of no benefit on account of their toxicity, such as stanuous chloride. At'tolerable doses it develops taeniacidal activity merely in combination with pelletierine which in itself is a remedy in the treatment of cestodes. The same applies to stannous oxide hydrate, the practical value of which depends upon the addition of pelletierine as an essential co-ingredient. Results with other tin comather erratic and inconclusive. If they shov' i an, their operative dosages lie too close to their toxic level in order to be recommended as vermiuges.

While, as already mentioned, a highly specific and sensitive relationship of action as a rule exists between the chemical structure of a drug and the physiological properties of a parasite in its host environment, it has been discovered that one group of compounds is capable of being applied against more than one species of infectious or ganisms. This surprising exception to the still valid rule or" drug specificity has hardly a precedent in veterinary medicine. No scientific reason can be assigned for this phenomenon. But the multipurpose use of these compounds in the prevention and cure of coincident infections by different parasites makes them of particularly 0utstanding value in the treatment of animal diseases.

No claim is made that the compounds of this invention constitute a panacea for all and any kinds of disorders although their effectiveness demonstrated in the hereafter exemplified cases may indicate their potential value for the control of similar pathogenic factors.

It is therefore one object of the present invention to propose a novel preparation for the prevention and suppression of certain protozoal infections in chickens and turkeys.

It is another object of the present invention to provide a remedy for the control of hexamitiasis in turkeys.

Still another object of the invention is to devise an anthelmintic agent against tapeworm and roundworm infections in domestic animals and birds, with particular adaptation to the removal of members of the genus Raillietina, such as Raillietina ccsticillus, and of the family of Heterakidae, such as Ascaridia galli, from fowl in an effective manner and without untoward reactions on the so treated animals.

Yet another and important object of this invention is the provision of veterinary preparations effective in the stimulation of growth, maturation, and resistance to infection.

Other objects and advantages and features of the invention will become apparent from the following disclosure which is primarily intended to l illustrative and not limitative in scope.

The active ingredients of t3. the essential components of ti imed composition can be broadly classified as new ty s of tetravalcnt tin compounds Which are best represented by the following configuration:

present invention forming wherein R and R are alkyl, aryl, aralkyl, or heterocyclic groups, and X and X stand for anionic radicals.

R and R may be either of identical structure or of dif-- ferent configurations, as the substituents have been found to be exchangeable for each other without substantially affecting the therapeutic properties of the compounds. The salient feature of this discovery is rather the appreciation of the fact that the molecular arrangement of two covalent organic groups in conjunction with two anionic portions attached to a tetravalent atom of tin imparts to the compound the desired pharmacological qualities. Any derivative of tetravalent tin having the structural pattern will produce the results contemplated within the purview of this invention; and whatever differences in dosages or potencies may appear to be between individual members of these groups, they are but variations in degrees conditioned by the specific substituents; but they are altogether included within a range of potency considerably below the toxic level which is characteristic of this type of compounds and distinguishes them from other tin cornpositions having a far narrower margin between therapeutic efiicacy and toxic reaction.

As previously stated, R may be represented by any substituted or unsubstituted alkyl group derived from the class of paraffins or saturated hydrocarbons. Examples of such residues are methyl, ethyl, propyl, butyl, amyl, hexyl, benzyl, and so forth. The group may comprise straight chain radicals Willi progressive sequences of carbon linkages, but it may also include homologous derivatives of chain and sidechain isomerism, such as 2'nethylbutyl or isopropyl. The nlkyl residues may further be substituted by vaitus other groups, such us by y. halogen and at in this ins position isomerism may occur depending upon where the substituent enters the molecule.

R may also stand for unsaturated derivatives of the parafiinic series which are commonly known as alkenes and alkynes. Both straight chain and isomeric substituents can be used within this group and in addition to the previously mentioned possibilities of chain and side-chain isomerism, representatives of position isomerism in the nucleus shall be comprised within the scope of this invention. Examples of this type of substituents are: allyl CH2=CH.CH2; l-butenyl CH3.CH2.CH=CH; and its homologous Z-butenyl CHsCI-I=CHCH2-; or 1- pentynyl CH3.CHz.CHa.CEC-, and its isomeric 2- pentynyl CH3.CH2.CEC.CH2.

As a further variation, R may constitute an alicyclic radical which has aliphatic characteristics, for example cyclopropyl and cyclohexyl.

Among the aromatic structures, R may be represented by any substituted or unsubstituted members of the benzene series, such as phenyl, tolyl, xylyl, and cymyl. Each of these residues may again be substituted both in the nucleus and in the side chain. Instead of the phenyl-ring radicals, the next higher homologues can likewise be used to advantage as exemplified by naphthyl and anthracyl, and their variedly substituted derivatives.

X may consist of any combination of elements capable of forming electronegative groups or anionic radicals with any given cationic portion irrespective of the degree of dissociation which such groups within the tin structure of the present invention may show in an electrolytic medium. As such X may consist of organic or inorganic radicals, including oxygenic and sulfidic groups. X and X collectively may be oxygen or sulfur.

Among the organic series the electronegative groups or anionic portions may be derived from aliphatic carboxylic fatty acids which are of saturated or unsaturated nature. They may be unsubstituted or substituted by hydroxy, amino, sulfo, halogen or other radicals in various manners known to those skilled in the chemical arts. Likewise X may be represented by diand poly-carboxylic acids of the saturated or unsaturated type in substituted or unsubstituted form, as illustrated by maleic, malic, fumaric, citric and phthalic acid. In addition to the aliphatic series, various aromatic anions may be used. They may have either carboxylic acid structure as in benzoic acid, or be derived from aromatic oxy-compounds as represented by phenolates:

Furthermore the organic anionic radicals may consist of aromatic sulfur derivatives such as benzene-sulfonates:

HG Eli and aromatic arsenic derivatives as typified by benzene arsonates:

Hi l

8 ing alcohols and form salts when treated with basic reactants which are called mercaptides. They ionize in aqueous media by separating into the cationic portion and the anionic moiety CHs-S'. As a further variety of this type of compounds, one or more of the hydrogens in the methyl radical may be replaced by the hydrocarbon portion of a carboxylic acid, its ester or salt and the resulting subsitution product gives rise to the formation of mercaptides of said acids, and esters. The simplest representative of such mercapto-acids is the mercapto-acetic or thioglycoilic acid HSCHZ.COOH.

It has been found that compounds of this type are of great therapeutic value in the treatment of the aforementioned infections. If, for example, 1 mol of di-nbutyl-tin sulfide is condensed with 2 tools of butylmercapto-acetate, the di-n-butyl-tin dimercaptide ot' butyl acetate will result, according to the following probable situation:

reaction of 1 mol of the dil (aryl or aralkyl) sulfide d mcrcapto-acid. These with 1 mol of an ll compounds have the property polymerizing to higher molecular aggregates and may L formed in the follow ing manner:

wherein x is a whole number greater than i.

From the proposed configuration of the condensation product it is apparent that herein the di-n-butyl-tin p01" tion with one valency forms the cationic base of a thio mercapto-acid while the other valence holds a hydroxyl group; the mercapto grouping -SH remains intact. The structure can be thought of as the re Iii of a molecular rearrangement whereby the hydroxyl of the carboxylic group -CO-OH attaches to the tin and the sulfur of the di-u-butyl-tin sulfide makes linkage with the carboxyl taking the place of the ejected hydroxyl.

in the event that one moi of an unesterified dicarboxylic acid enters into reaction with one mol of dialityl-(aryl or aralkyl} tin sulfide, one of the valences will form a true salt with one of the carboxyls, while the other valency replaces the hydroxyl of the'carboxylic function. If mercapto-succinic acid is used for condensation, the following configurations are possible:

m- ...MWWMM. a, F in till This condensation product which has the tendency to polymerize may be considered as a di-n-butyl-tin mercapto-thio-succinate, x representing a whole number greater than one.

Another group of sulfidic compounds included within the purview of this invention are the polymerized di-alkyl- (aryl, or aralkyl) tin alkoxide-mercaptides which form by condensing 1 mol of the tin-sulfide derivative with 2 mols of an alcohol as illustrated by the following equa' tion:

GHs(CHc)a HO-CaHs CHKCHQA S-CsHs 2:

wherein x is a whole number greater than 1. In this particular instance the product may be regarded as a di-n-butyl-tin cthoiride-ethyl-niercaptidc.

It should be understood that the above given formulations are presented by way of illustration only and should not be construed as limiting upon the coverage of this type of compounds. Their identity is primarily determined by the indicated mode of preparation in reciting the molecular proportions of the reacting partners. Thus reaction products of 1 mol of di-alkyl-(aryl or aralkyl) tin sulfide with 2 mols of an esterified or neutralized mercapto-acid, or with 1 mol of an unesterificd mercaptoacid of either monoor polycarboxylic structure, and with 2 mols of an alcohol respectively are here claimed as coming specifically within the purview of our tetra valent tin remedies, wherein the di-alkyl-(aryl or aralkyl) portion is attached to an anion. Irrespective of the position of the mercaptide, alcoholate or acid ester linkage in the molecule, all three of these functions are obviously anionic in nature and therefore properly fall Within the category or" compounds as previously defined.

in the inorganic class, X may stand for halogen and oxygen containing acids, such as chlorides, bromides, iodides fluorides, and sulfides, sulfates, nitrates, phospirates, chi "*es, arsonates, antimonates and many others. ll 15 in the case of R, ditierent acid radicals may paired X, or one of them may be combined with an oxygenic group in a composite structure. Oxygenie residues may be derived from stannic acid formations such as found that certain complex or polymerization products provide an additional variety of excellent veterinary drugs. instances of such complex formations are:

t It? X1 RL-O /Sn-O-- R5 /Sn\ QR? n R4 X1 where R R R and R may be one of the above scribed hydrocarbon radicals; R may be hydrogen or a hydrocarbon radical; X and X may be halogens or other anions herein described; and n is a number or improper fraction from 1 to 20, preferably from 3 to 10. Tetravalent tin compounds of this configuration have been disclosed in United States Patent No. 2,604,460.

Hydrolysis in aqueous alkaline solution to dihydrocarbon-tin oxides of varying degrees of polymerization is characteristic of this class of complex tin derivatives. Th tendency of monomeric dihydrocarbon tin oxides s of varying degrees of polymerization by Smith and Kipping in 3. Chem.

arouses 9 Sec. (1913), 103, 2034, 2050, wherein the resulting prodnets are characterized as closed chain polymers, such as It has likewise been shown in United States Patent 2,626,953 that monomeric dialkylor diaryl-tin-dialkoxides which are regarded as others of a polystannanediol may form open chain composite structures of more than 1 and up to units depending upon the conditions of temperature and heating time controlling the reaction. In this manner pure polymers or mixtures of polymers While compounds of this type have here been ex: pressed in terms of simple oxides for the purpose or uniformity, such as di-n-butyl-tin oxide, dibenzyl-tin oxide, di-n-butyl-tin dibutoxide and the like, it is not intended to limit the invention to their monomeric state, and wherever the disclosure refers to dihydrocarbon tin oxides or to derivatives of dihydrocarbon stannancdiols, their polymeric condensates are meant to be included. It is readily apparent that the basic configuration of the claimed compounds wherein R and R are hydrocarbons and X may stand for oxygen, is not affected b the status of polymerization, since the primary str unit is maintained un changed in all the polymers The compositions of the t -regoing description are all comprehended within the hr and generic concept of the present invention which, through many hundreds of experiments, is predicated upon the findings that the na' ture of the substituent has no material bearing upon the pharmacological properties of the compounds; the therapeutic action substantially depends upon the basic configuration as drawn to a tetravalent tin derivative with two of its valencies connected with an allcyl, aryl, arallzyi, or heterocyclic group, and its two other valencies linked to an electronegative or anionic portion. This discovery provides a large choice of remedies for an efiicient stannotherapeutic treatment of multiple infections which up to this time has been unavailing because of the high toxicity of the materials hitherto used.

For illustrative purposes, the following compounds are listed as representative members of the series found to be useful within the purview of this invention:

Di-n-bntyl-tin di-(3-nitro-4-amino-benzene)arsonate Di-n-butyl-tin diphenoxide Di-n-butyl-tin dibutoxide Din-butyltin dimethoxide Di-n-butyl-tin (hydroxy)-mercapto-thio-acetate condensate from 1 mol di-n-butyl-tin sulfide and 1 mol mercapto-acetic acid Di-n-butyl-tin di-(mercaptide-iso-octylacetate) condensate from 1 mol di-n-butyl-tin sulfide and 2 mol iso-octylmercapto-acetate Di-n-butyl-tin di-(mercaptide-ethyl-ltexyl-succinate) condensate from 1 mol di-n-butyl-tin sulfide and 2 mol ethyl-hexyl-mercapto-succinate Di-n-butyl-tin di-(mercaptide-octadecyl-succinate) condensate from 1 mol di-n-butyl-tin sulfide and 2 mol octadecyl-mercapto-succinate Di-n-butyl-tin di-(mercaptide-Z-butyl-octyl-succinate) condensate from 1 mol di-n-butyl-tin sulfide and 2 mol 2-butyl-octyl-mercapto-succinate Di-n-butyl-tin di-(mercaptide-octadecyl-acetate) condensate from 1 mol di-n-butyl-tin sulfide and 2 mol octadecyl-mercapto-acetate Di-n-butyltin mercapto-thio-succinate polymer condensate from 1 mol of di-n-butyl-tin sulfide and 1 mol mercapto-succinic acid Di-n-butyltin di-(mercaptide-butyl-acetate) condensate from 1 mol di-n-butyl-tin sulfide and 2 mol butyl-mercapto-acetate Di-n-butyl-tin ethoxide-ethyl-mercaptide polymer conden sate from 1 mol di-n-butyl-tin sulfide and 2 mol ethyl alcohol Di-allyl-tin dilaurate Di-etliyl-tin dilaurate Di-mcthyl-tin dilaurate Di-methyl-tin diacetate Di-amyl-tin dilaurate Di-amyl-tin-maleate Di-n-butyl-tin oxide Di-n-butyl-tin stannonic acid Di-n-butyl-tin sulfate Di-mbutyl-tin dichloride Complex di-n-butyl-tin oxide-dichloride polymer Di-n-butyLtin dihydrogenphosphate Di-n-butyl-tin difluoride Di-isopropyl-tin di-ioclide Di-carbethoxy-ethyl-methyl-tin dibromide Di-lauryl-stannonic acid Di-phenyl-tin dilauratc Di-phenyl-tin diacetate Di-phenyl-tin dichloride Di-phenyl-tin oxide Di-benzyl-tin dilaurate Di-benzyl-tin diacetate Di-benzyl'tin dichloride Di-benzyl-tin oxide Di-parachlorobenzyl-tin dichloride Di-para-chlorobenzyl-tin oxide Di-methyl-tin di-iodide Di-ethyl-tin di-iodide Di-amyl-tin di-iodide Di-lauiyl-tin dichloride In order to accomplish the objectives sought by this invention the foregoing compounds are administered orally to the animals in critical amounts so as to pro the beneficial effects of anticoccidial and anthelm activity, the prevention and control of hexamitiasis an the stimulation of growth.

Conveniently the mode of administration consists in incorporating the active ingredients into a feed ration in such amounts as to provide a daily minimum intake thereof required by the particular disease or the desired physiological function, hereinafter more fully explained. Rations suitable for medication comprise such elements of sustenance as grain, mash, and scratch for fowl, dog feed and similar animal foods. When administered in the feed, the compound may be first mixed with a small quantity of an inert carrier like fullers earth or bentonite or any other suitable diluent. This mixture is then introduced into the ration with thorough stirring and shuffiing until a uniform blend of even distribution has been obtained.

According to our invention the remedies may also be associated with liquid carriers like water and such coroit it positions may be in the state of solutions, dispersions or suspensions, or other dosage forms which are particu-' larly useful for imbibition. Stable suspensions of some of the less soluble compounds can be obtained by the addition of emulsifiers among which polyoxyethylenelauryl-ether and Emulcol 11-72, a condensation product or a fatty acid with a polyhydric alcohol, are most suitable for practical purposes. Other liquid vehicles for medication may be edible oils, such as olive, peanut, coconut and cottonseed oil wherein the tetravalent tin compounds may be dispersed. Various other orally ingestible diluents may likewise be used.

Although the compounds are advantageously given in the normal diet of feed, water and similar elements of sustenance, they may also be dispensed in individual, unitary doses. Such an alternate form of treatment is of particular value for the elimination of intestinal worms when a speedy removal effect is desired and the size of the iiock or the type of animal does not warrant the formulation of solid or liquid medicated rations. Individual doses may take the form of capsules, tablets, granules or powder. When administered in tablets, the same may contain any diluents or ingredients which will impart to them the necessary stability, consistency, cohesion, lubricity and other desirable qualities. Materials used for that purpose are talcum, stearic 1010 and its salts, such as magnesium stearate, gums, lactose and cornstarch. However we have made the interesting observation that some of the tetravalent tin compositions, like di-nbutyl-tin dilaurate, do not seem to require a lubricant, as they are themselves capable of: developing that property in a tablet. Other unitary dosage forms may comprise a gelatine capsule including the active ingredient in dry or liquid suspended state, or crumbles prepared with the aid of inert fillers and a binder.

The effective dosages fc most favorable results will be illustrated in fowl and although it is not intended to limit the invention solely to these particular species of animals. The criterion for proper dosing is the determination of the daily minimu equirements per kg. body weight of the animal for desired therapeutic treatment; these minimum amen however, may vary in accordance with the age, w ht and breed or" the specimen treated. it is only ssary that the drug constitute a proportion of the ed vehicle so as to provide an adequate dose for no animal consuming it when allowed to feed ad libitum on its normal diet.

it has thus been found that the smallest daily amount active ingredient required to stimulate growth and maturation in chickens is 1 mg. per kg. body weight, when feed is the vehicle of administration. in order to supply this minimum dosage of daily drug intaloe the compounds would have to be added to a normal reed ration in a ratio of approximately 0.002%. The concentration may be raised with equal beneficial effect up to 0.05% which amounts to a daily dose of approximately 70 mg. per body weight. Gptirnai results were obtained with ratios between 0.01% and 0.05% when the treatment was continued for five weeks.

Each test in the following growth studies involved newiy hatched chicks of a given breed which were divided into two groups one of which was treated white the other served as unmedicated control. From care fully maintained weight records the mean weight gains of the birds in the treated and in the control groups were determined and the ratios of weight increases calculated. These figures multiplied by 100 represent the percentages 01 eight gains attained by the treated birds as com pared with the untreated ones. Thus, if the average gain for a group of treated chickens was found to be 348.3 gm. and the gain of the controls 252.8 gm, the percentage of weight gain, expressed as Ratio 170% would be:

ted diet. 1

12 while Group 1 showed a weight increase of 348.3 3111. and Group 2 a gain of 344.3 gm. It follows that the "Ratio T/C for a concentration of 0.01% was 137.8% and that for a concentration of 0.02% was 136.2%. Ad-

5 ditional test data on the tonic effects of other compounds in different proportions are summarized in Table I.

Table I Avg. In 1 t d' t i (Yin 'i l'( 5, 00 CH- on 0 No. Lompound Per Period, Per Pen cent Weeks Bird, cent Grams lo 0. 0025 5 302 113.1 0. 0050 5 303 124. a 5 402 125.0 5 331 122.0 5 5 351 110.0 5 307 121.0 5 370 114.0 4 5 309 1120 2-1 Nona--. 5 329 Dimolzhyltm dl-1odlde. 0.0020 5 360 114.8 5 303 110.0 5 374 110.2 5 332 110.0 5 s21 5 375 121.0

Similar good results of stimulative action are obtained with medicated water when a daily minimum dosage or": 2 mg. per kg. body weight is provided. border to as sure a drug intake on that level, a suspension having a strength of at least 0.0025 is prepared and altered to the bird for imbibition ad libitum for the duration of the test. The strength of the drinking potion can be raised up to 0.06% corresponding to 140 mg. per kg. body weight as shown in the following example.

EXAMPLE 2 In all the tests tabulated hereafter, equal numbers of threeday-old New Hampshire chicks, on the average between 24 and 30, were used for the experiment and subiected to a five-week treatment with varying proportions of medicated drinking suspensions. They were formulated by diluting 51.2 grams of the compound with polyoxyethyiene laurylalcohol to a final volume of 100 cc. Gne fluid ounce of this solution to 20 gallons of water yieided a concentration of 0.02% of the compound. A stable dispersion may also be obtained by the use of an emulsifier known as Emulcol H-72 which is a condensation product of a fatty acid with a polyhydric alcohol. The Iollowmg table shows the growth efiects 0 chieved with various compounds and concentrations:

Table 11 Avg. {)3 B d 050. Medlgift. R F/tic,

1r 5, ater, cation aln C No. Compound Per- Period, Per Percent Weeks Bird, cent.

Grams 30 Di-nbutyl-tl11 dioleate 0. 0000 5 373 110.2 80. .(10 0.0400 5 391 115.7 0. 0050 5 382 113. 0 0. 0025 5 375 111.0 5 338 0. 0400 5 338 120. D. 0. 0200 5 390 123. 0 7 0. 0050 5 380 120. 0 0. 0025 5 377 117. 0 25. None 5 322 24. Dl-n-butyl-tin dilaurate 0. 0500 5 364 109. 6 24. ..do. 0. 0400 5 372 112. 0 0. 0100 5 351 114. o. 0050 5 371 112. 6 r. 5 332 w... 0. 0100 5 372 109. 2 0.0200 5 380 111. 8 0. 0050 5 384 113. 0 0 0025 5 378 111.0 .1 5 340 For turkeys the daily minimum intake required for stimulative effects is approximately 4 mg. per kg. body weight or 0.005% in the feed. The ratio may be raised to 0.15% with equally favorable results. It is apparent that turkeys require somewhat larger amounts of the active agents to produce the same benefits in view of the physiological peculiarities of this avian species.

EXAMPLE 3 Ninety Beltsville White turkey poults were divided into three groups of 30 birds each. Two groups received a feed ration containing din butyl-tin dilaurate a level of 0.05% and 0.005%, respectively, while the third group served as control and was kept on an unmedicated diet. The experiment was conducted continuously for a period of five weeks at the end of which the weight gains were established for all the three groups. The average weight increase for Group I was 587.1 gin, that for Group H was 475.4 gm, and the gain for the control group amounted to 399.7 gm. In accordance with the above outlined equation the T/C per cent ratios for Groups I and II are found to be 146.8% and 118.9%. Additional growth tests are summarized in the following table.

Table III Avg. Bi ds ti' Midi. o /ii r ee out on a n No. Compound Per- Period, Per Per cent Weeks Bird, cent Grains DI-n-butyl-ttn dilaurate... 3 ,do 3 None 3 Di-n-butyl-tln d 4 None r 4 Di-n-butyl-tin oxide--. 5 None 5 Di-n-butyl-tin di-olente. 3 None 3 Di-n-butyLtin distearutm. 3 N one 3 Dl-n-butyl-tiu sulfate. 3 None 3 Di-n-butyl-tin dibutyrate 4:. 050 3 None 3 Dl-n-butyl-tim-niiro 025 1 benzeneursonate. None 4 Di-n-butyl -ti 1-4-11ltro' 0.020 4 benzenenrsonato. None 4 i The effective dosage for the suppression and control of coccidiosis in chickens has been found at a minimum level of 12 mg. per kg. body weight daily intake. A preferred dosage range lies between about 12 mg. and 700 rug/kg. body weight of the compounds administered in medicated feed containing snlicient proportions to secure ingestion of these amounts by daily consumption.

More specifically it has been discovered that, While partly overlapping, the ranges applicable to Eimerio .necarrix and Eimeria zenella infections show only slight variations which are due to the nature and degree of virulence of each of these two etiological factors.

For Eimeria necatrix the minimum dosage required for effective treatment is approximately 12 rug/kg. body weight per day and can be increased up to 550 mg, cor responding to a feed concentration of 0.025% to 0.4%. The corresponding minimum for the control of Eimerio renal/n amounts to 19 rug/kg. body weight and might have to be raised up to 700 in the event of a heavy infection of long standing. in order to afford a daily intake of that dose a feed concentration of 0.0375% up to 0.5% is required.

CAMPLE 4 organisms of Eimerz'a necatrix capable of killing approximately 75% of the controls which were infected simultaneously with the test animals. The test group was kept under treatment for 13 days. The following table shows the type of medication and its concentration used, the numerical relationship between the number of sur vivors and that of the entire treated group, and the ratio between survivors and total controls in the unmedicated group. A comparison of these figures immediately reflects the comparative mortality rate between the treated and untreated birds.

Table IV N0. Survivors/Total Cone. No. Birds Compound Feed,

Perm Treated Untreated Group Group Dlphenyl-tln oxide 0.100 4/4 1/4 D 0. 050 4/4 114 Do 0. 025 3/4 1/2 Di-n-butyl-tin otecetate 0.100 4/4 11: Do O. 050 4/4 1} i Dl-n-butyl-tln dllaurate. 0. 400 4/4 2/4 Do 0. 200 4/4 2/ Do.-- 0.100 4/4 2/4 Do r. 0.050 4/4 2/1 Dl-n-butyl-tin dl-4-nltro-benzone-a.r-

sonata 0. 100 4/4 1]: Do 0. 050 2/4 1/4 Dlbenzy1-tln dichloride. 0.300 4/4 2/4 Do 0. 200' 4/4 2/4 0.150 4/4 2/4 Do 0. 100 4/4 2/4 EXAMPLE 5 An even number of New Hampshire chicks arated into equal groups one of which was kept s trol while the rest received a medicated feed ration raining varying doses of 0.0375 to 0.5% of one of tetravalent tin compounds. Three days after the bu Were placed on their diet, all the groups were infected with 100,000 oiicysts of Eimeria tenella and treatment was maintained for 11 consecutive days. The following table shows the results under headings corresponding, to those in the previous example.

Table V As for coecidiosis in turkeys, the minimum daily dosage required for control has been found to be nag/kg. body weight and may have to be extended up to 230 rug/kg. body weight according to the breed of bird and the severity of the infection. Investigation has forth r shown that due to the biological differences of t pathogenic factors, Eimeria'meleagridis requires a little lower dosage than Eimeria meleagrimitis. For the former a daily minimum requirement of 10 mg. has been determined of sufiicient incipient potency, while the latter necessitates a critical minimum of mg./kg. bod weight. Preferred concentration ranges in accordac. with these critical values are 0.0125% to 0.2% in- Eimeria meleagridis and 0.025% to 0.2% for Eimerr'o meleagrimitis.

EXAMPLE 6 Forty-eight New Jersey Buff poults were segregated into twelve groups one of which was set apart as control. The remaining groups were placed on feed medicated with varying doses of tetravalent tin compounds ranging from 0.0125% to 0.2%. After three days of treatment all the birds were infected with ;"00 sporulated oocysts of Eimeria meleagridis and cont u otisly kept on medicated diet for the duration of i3 days. The following summary shows the mortality rates 16 Table VIII in the same manner as in the foregoing experiment.

No. Survivors/Total Table Vi com Nmmrds Compound Feed; No. srtirvllvtlarrglslotal Percent Treated Untreated Cone. Group Group Compound Pl eed,

amen Treated Untreated Dl- -bnt l-tln dlstearate 0.1000 4/4 0/4 GIMP no Z 0. 0500 3/4 0/4 Dl-nbbutyl-tm dl-oleate... g. ggg O mnbbulyl'm 1118mm 8- Dl-n-butyl-tlnn1nleate. 0.0500 4/4 0/4 g- 010500 4/4 1/4 lDi-n-butyl-tln oxide.... 0. 0500 4/4 0 4 DQII 0. 0010 4/4 1/4 3 gggg DgIIIIIIIIIIIIL. 0101215 3 4 1 4 pl-n -lliiiyl-tln dildn 0' 0500 4/4 1/4 dmmmde- 8- it: n I. o I b'g' dltmmlde- Dl-n-butyl-tln (llvtllel'iltG. 0.1000 4/4 2 4 13 0 0125 4/4 1/4 D b (Meme 8- 888 if: 0 0 0500 4/4 1/4 .Dl-n-butyl-tln dlheptylate 0.1000 4 4 2 4 Di-n-butyl-tln (hydroxy) mercaptothgacetate polymer flggg 1 O EXAIVIPLE 7 0 1 5 2/4 i The same technique as in the previous example was 3 23; 52 3/; used to demonstrate the efficacy of our new remedies 25 0.0500 4 4 0 4 against Eimeria meleagrimitis. The concentranons 1n the 8-8238 if: 2;: feed varied between 0.025% and 0.2% in conformity M 3/4 0/4 with a daily minimum requisite of 20 m x/kg. body 0.0100 0/4 0/4 weight which may be increased up to 230 mg. per day. M063 0/4 For artificial mfection, a preparation of approximately Stu/0mm 0.1000 4/4 1/4 400,000 sporulated oocysts of the organ sm was em- D1 D 8.0888 g7; 1

-Il- 1.1 y -ll1Sll 8/ 8 Ployed. The results are summarized below. nbmbnymm 0 0 00 4/4 0] S0115- B l Table D0 0.0250 21 4 0/4 Di tl iifdis u 4"iri 0' M125 2/4 s -l'lutyll -D 10- 3m 0' 911- fi gggg zene-arsonate. 0.0250 3/3 0! Gone. Do 0. 0125 1/4 0 Compound Fee/d, Dij-n-butyl-tln dl-3-nltro-4-hydrorq7- 0 0500 14 014 Percent; n e nzene-arsonatm 5533 9 flfgfig Do 0. 0250 1/4 o 4 iiifi fiiiifiiiiiii iii iii EXAMPLE Q Water medication at 0.1% to 0.02% concentrations 4/4 1 4 was tested in a similar manner as in the preceding expertntent. The chemoprophylactic potency and control efiect 4/4 appears from the foilowmg table.

The prevention and control of hexamitiasis in turkeys Table IX calls for a daily minimum intake of 10 mg. ot the comr0 pound per kg. body wei ht in the feed and about 45 mg. a No Survivors/Total in the water. Optimal results are obtained by a feed Cone N0. Birds ration providing the medicament at a daily rate be- Compougd w r tween 10 and 230 mg/kg. body weight or 0.0l25% to P r nt Treated Untreated 0.2%. When given in drinking water, the preferred Group Group dosages lie between 45 and 360 rug/lag. body weight p r y, wh h ll be pp y a g h Of 002% DLn-butyI-tin dilaurate 0.1050 3 0, to 0.1% of the aqueous preparation. As in the pre- Do 0.0025 4/4 0/4 vious tests the etlicacy of the drug was ascertained on g3 r 383?; 2;: 8;? the basis of comparative survival rates of the medn fjfjjjjj @0200 3/4 icated-infected and the nonmedicatedinfect ed groups. A u uniform pattern of high mortality rates 1n the control g p PP W pfevalls- AS l lnclflwtal advamagfi, As previously mentioned, the stannotherapeutic come It has H150 n noted h the g $31115 0f h treated positions of our invention provide, besides their remedial flmmals'wiifd F P Y $Sla1f1ed and at llmfis U5 and preventive action, an additional benefit by at least sPbstflnilally lncfefiwd dfisplte the 080301021681 COMM" sustaining and sometimes even considerably promoting tron. the growth rates of birds afflicted with disease. Special EXAMPLE 8 investigations were carried out to demonstrate this effect A flock of about three-week-old Beltsville White tura the concentranons e p for the p p ltey poults was divided into groups of three and four 10m} to the levels established for the control of the varinnimals each and a number of control groups wars 011$ infections illustrated in 0111 PREVIOUS examples. segregated from the test batch. All the birds were place v on medicated feed added with 0.012590 04 0.2% of dif- EAAMPLE ferent tetravalcnt tin der1vatives. Three days after the A ill b Seen f h fongwing t bl h ti l t. treatment was started, all the birds were infected w th 7 inghand growth sustaining ff ts unde? diff h an lmclllum P PP from R ileum of sPeclmens which logical conditions are computed in relation to the normal had recently d ed of hexamltiasis. The ilcac fragments growth rate of an untreated and noninfected bird. Thus, were (lllCClly lfiIl'OClllCCCl Into the crop oi the animals. besldes the infected and treated test group, two instead All the poults were weighed periodically, and lead and of one control groups were assigned to the test, one of water consumption records were carefully kept on a which shows the weight galns or losses of the infected- Duily observations were made for the weekly basis.

.s such s l:

sence of clinical sympto 5a, droopmes A we 9/ Wilma...

neonate for days with a basal ration containing 0.025% of di-n-butyl-tin dilaurate, the average weight gain at the end of the period has risen to 22 gm. Without any medication an infected animal not only failed to gain, but registered a weight loss of 25 gm. and lapsed into a state of progressive emaciation. A normal and untreated turkey on the contrary reached a weight gain of 155 gm. in comparison with which the gain of 229 gm. of the infected and medicated animal represents a T/C ratio of 147.89. Differently stated, in spite of the disease a medicated animal still shows a meat producing capacity of nearly 50% above that of a normal bird which does not receive the benefit of the treatment.

As may he expected, the stimulative action of the compounds is not of the same potency under all conditions of disease. They will sometimes just sustain the normal rate as illustrated by a T/C ratio of only 103.2 in the case of hexamitia is under the eifect of di-n-butyl-tin dichloride. if a Cll'IldJUiyl-dlll (hydroxy)-mercaptoacetate polymer is the remedy of choice, growth can be intensified at least to the extent of 53% of the normal rate, while the denial of any medication to an infected bird would raise its weight to no more than 7.2% above the starting level. It follows that reasonable allowance should be made orally ingestible material or pharmaceutical carriers like gelatine, oils and other carriers known in the veterinary arts as suitable vehicles of medication. Dne or more single dosages may be manually forced into the animal's digestive tract. The remedy may, for instance, be included in solid form in a gelatine capsule, or it may be dissolved or dispersed in an appropriate liquid to be worked into a gclatine pearl. In other cases it may be advantageous to administer the compound in form of a tablet prepared in conjunction with suitable tablet forming ingredients as previously described.

The minimum single dose of vermifugal medication is 50 mg/kg. body weight. In practice, however, this quantity may have to be increased up to 400 mg. for higher efficacy, depending upon the kind of animal treated, its breed and age, the heaviness'of the infection and the potency of the specific agent involved. Obviously, eral dosage units below the specified level may be given at about the same time to total an aggregate of the required minimum intake. Thus, for example, if manufacturing conditions or the technique of dispensing the drug make it more expedient, two dosages of mg. i stead of one of mg. may be applied simultaneous or within a short time interval. A minimum dose of for variations in potency of the tin remedies, which 25 ing/kg. body weight corresponds to an amount of 3 mg. likewise explains a flexibility of dosages to be applied per dosage unit for a one week old bird of about gm. within the illustrated ranges. (See Table X.) The tolerated doses may depend upon the stram or Table It 31 Cone Medlctr Avg. Wt. Ram

. Disease Compound Feed, g g ggfig 'IIO Type No. Percent w} Grams Percent Turkeys 4 E. meleuyridis Dbn-bufiyl-tin dileurzite 0 1000 10d 229.0 148.8 D 4 dr (1 179.0 115.5 4 210.0 135.5 4 229.0 147.8 .1 25.0 4 155.0 4 192.8 60.8 4 252.5 79.0 4 255.7 80.7 4 6.0 4 317.3 4 E. meleagrimzt 13 2 90. 7 4 d 32.7 4 149.0 251.7 2.9 4 235.3 152.9 4 212.7 7.7 4 24.5 4 o 154.5 4 Diat-butyltin dichloride. 525. 3 103. 2 4 None a. 233.8 4 .d0 509.2 4 lti-n-butyl-tin di-aceta s. 468.2 92.0 4 None 238.8 i .-do 509.2 4 Di-n-butyl-tin (by roxy)met- 281.3 52.6

captoacetate polymer. 4 None 40.0 a do 553.7

I (1. means days and w. means weeks.

We have also discovered that certain new types of tetra valent tin compounds are particularly useful and efiicient in the chemotherapeutic control of helrninthic infections. Their superiority in action resides in a surprisingly high therapeutic index, a high degree of palatabllity and a more universal range of applicability with respect to a wider variety of worms. The novel tin compounds have a toxicity level far below that possessed by other tin compositions, and manifest at the same time such a high degree of potency that even relatively small dosages of them yield the full benefit of their remedial function. As already demonstrated in reference to other diseases, the compounds have no harmful effect upon the well-being, growth or maturation process of the arintals when given under repeated or extended single dose medication due to the favorable relationship between toxic level and vermifugal efiicacy. Their activity is directed both against cestodes and nematodes. It is, therefore, possible to con1- bat successfully by the same treatment a mixed infection of poultry with roundworms and tapeworms such as is frequently produced by a concurrent invasion of Ascaridin galli and Raillietiim cestz'cillus.

'1' net" breed of the animal, the experimental environment the nature of the compound involved. These factors well known to or readily ascertainable by a skilled wt in the veterinarian arts. It has been found that l Hampshire and White Leghorn chicks have a somew higher tolerance for the tetravalent tin derivatives of invention than the Ames lit-Cross or Nichols sha whichare more sensitive to dosages above to mg./kg. body weight. Respecting the possible ham ul properties of the compounds, it has been previously observed that the materials as a group possess a relatively high threshold of toxicity. Investigations have shown that some representatives of the series, such as (ll-314L 12 tin dipalmitate, di-oleate, dimaleate, and sulfide, lau or phcnylstannoic acid, dilauryl-tin oxide and others may be administered without adverse effects in unitary dosages up to 1500 and 2500 mg. and more per kg. body weight. it should, therefore, be noted that amounts of more than the specified ranges will generally be harmless so that in practice only minimum levels need be considered as criti' cal, with the only exception of methyl derivatives. is well known to pharmacologists, physicians and veterinarians that methyl compounds are ordinarily more toxic than the homologous alkyls of higher molecular Wei acetate should be used at levels substantially not exceeding the base limit of 50 mg./kg. body weight.

An increase in dosage may also be indicated to combat a relatively heavy load of Ascaridz'a gnlli in the presence of cestode infection.

When given in the feed for the elimination of internal parasites, rations containing the drugs in an approximate minimum concentration of 0.05%, corresponding to a daily intake of about 25 mg./kg. body weight, have produced excellent results after consumption ad libitum for one or two days. Here again, however, some variations may occur with respect to dosage and duration of treatment according to the type of animal, compound, and nature of infection. In some cases the full benefit of the remedy required a concentration of 0.2% and more.

The following tabulations are representative of some preferred embodiments of the invention applied to anthelmintic treatments which herein shall be illustrated on poultry without, however. thereby limiting the scope of this invention In fact it has been found that the tetravalent tin compounds according to our invention may be used with like advantage for other animals like dogs, sheep, cattle and swine and will display their vermifugal activity when applied in proper dosages which can be readily determined by those skilled in the art.

Experimental infection of the birds with Ascaridia galli was carried out by placing a given quantity of embryonated ova in a small amount of feed which would be consumed by the birds within one or two hours. The number of embryonated eggs varied from 750 to 1500 per bird. The age of the birds so treated was about 10 to 21 days. In order to establish the degree of efiicacy of the test compound all the droppings eliminated from the experimental animals for at least three days after medication were carefully examined for Worms and their numbers recorded. In this manner the number of worms removed by the treatment was found. When the fecal material no longer showed evidence of worm discharge, the birds were sacrificed and the intestinal tract was examined for remaining worms. Their number added to the number of parasites removed was considered as the total present before treatment was started and the ratio between the total number and the fecal eliminates measured in proportion to 100 defined the percentage of eificacy.

For Raillzetinn cesticillus the birds were given about 50 cysticercoids and the presence or" infection was established after about one month by examination of the droppings for segments. The birds were divided into two groups one of which was treated with the compounds of our invention and the other remained untreated and served as control. After 14 days all the birds were killed and necropsy was performed to determine the number of tapeworms retained. The number of parasites found in the untreated group was taken as the probable amount of infection which in comparison with the number of worms unremoved in the treated group, referred to 100, measured the anthelmintic activity of the tested drug.

When the remedy was given in capsule form. feed was withdrawn from the birds at about p. m. the evening preceding the administration of the drug. On the day of treatment the birds were weighed and the suitable amount of drug, calculated on the basis of the re uired minimum dosage, was placed in the capsule which was then forced into the throat of the animal. In case of feed medication. no previous starvation is required. The birds were weighed in the morning of the treatment and the unmedicated feed was removed. The medicated feed was then weighed into individual cups and placed before the birds. Feed weights were determined at regular dailv intervals at the same hour.

The first two of the followin tables shows the anthelmintic etlicacy of a great variety of our new remedies in their action upon the tapeworm or Rnillictina Ceslz'cilllls in poultry. The first column gives the ratio between the total number of experimental birds and the number of proven infections. Next are listed the name of the drug applied and its dosage. In Table XI, showing the results of capsule treatments, the dosage is expressed in mg. per kg. body weight (dose. mg./kg. body wt.). Table XII. illustrating the administration by feed. lists the amount of drug per l00 grams of feed (dose, mg./l00 gm.) and in addition the calculated total close consumed by the bird :1 period of one or two days f tfcale. dose l:

the aforementioned daily weighings of the feed cups. Thus 1 designates the amount of 50 mg. drug per 100 grams of feed during a period of one day, 50/2 the same dosage administered for two days. The last two columns of Tables XI and XII record the number of tapeworms found at necropsy and the efficacy in per cent as calculated from the base figure of the unmedicated controls listed in the last horizontal line of each experiment.

Tables XIII and )GV follow the same arrangement as that of the two preceding tables. They tabulate the results obtained in the removal of Ascaria'ia galli, Table XIII by capsule and Table XIV by feed medication. The dosages for capsule and feed are reported under corresponding captions as in the preceding tables, followed by columns listing the total number of ascaridiae as previously explained in the outline of the procedure. The next following column registers the number of parasites removed and found in the droppings; the last column gives the per cent of efficacy as computed from the two last named figures. (See Table XI).

Table XI CAPSULE MEDICATION FOR RAILLIETINA C'ESTICILL US Tape- No. Birds, gfi g worms 5:? No. In- Compound Bo'dy at: Neci feetod Wt 1% 27, cent Dlcthyl-tln di-iodtde 100 0 100 ..-..do 200 0 100 Unmodlcated controls 193 100 0 10B 200 0 mt: Unmedtcated controls.. 64 Dt-nllyl-ttn dilaurnte... 100 101 do 200 40 Unmedlcated contro1s.. 216 Dl-n-butyl-tin dichloride. 100 0 100 .do 200 0 100 Unmedtcated controls 271 Dl-n-butyl-tin oxide 100 16 82 o 200 0 100 Unmedicated controls.. 271 Di-n-butyl-ttn dttormate. 100 5 97 -do 200 0 100 Unrnedicatcd controls n 379 Di-n-butyl-tin diaceta 100 1G 76 d 200 2 9B 72 100 3 Bl. do 200 0 100 Unmedicated controls 57 Di-n-butyl-tin di-nbutyrote 100 2 94 do 200 0 100 Unmedieated controls 57 Di-n-butyl-tln di-n-volerate 100 33 51 ---do 200 14 59 Unmedlcated controls 118 Dl-n-butyl-tin di-n-caproate. 100 6 88 .....do 200 6 88 Unmedicatcd controls 118 Di-u-butyl-tin di-n-heptylate.. 100 38 44 .....do... 200 1 no Unrneclicated controls 118 Di-n-butyl-tln dl-n-caprylate..- 100 5 96 ..-..do .---200 0 100 Unmedicated controls 379 Di-n-butyl-ttn dipelargonate 100 18 73 d0 200 8 7o Unmodlcated controls 118 Di-n-butyl-ttn dipelar note 400 0 100 Unmedicated controls... 164 Di-n-butyl-ttn dicaprate 9 87 0 0 100 Unmedlcated controls 118 Di-n-butyl-tin dt-undecylenate. 100 35 12 do 200 20 57 Unmedicated controls Di-n-butyl-tln dilaura Unmedicated controls. Dl-u-bu tyl-tln dilnura Unmedicatcd controls. Dt-n-butyl-tin dilaurate. Unmedieatcd controls.-. Di-n-bu tyl-tln dilnurate. 200 Unmedlcated controls-.. Di-n-butyl-tin maleate.. 100 Unmedicated controls 15 Dl-n-butyl-tin dimsleate 200 0 100 Unmedicated controls 219 4/4 Di-n-amyl-tiu dl-lodide.... 100 53 4/4.... ...-do 200 3 97 6/6 Unmedicated controls 174 4/3 Diphenyl-tin dichloride. 100 0 100 4/2.. d0 200 0 100 8/7. Unmedicated controls 118 4/4 Di-bcuzyl-tin dichloride... 160 0 I00 ....-tl0 200 0 1G!) Unmedicated controls..- I. Dl-ctbyl-tiu dilanreto O 106 23 Table XIH-Continued.

CAPSULE IMEDICATION FOR ASCARIDIA GALLI 24 a comparing eficaey figures for capsule and alimentary treatments, it appears that some of the compounds develop a greater potency when given in the feed than No. Total Em when adn 11n1stered m s ngle medlcatlon un1ts. For ing C d 7 f/1 s cacy, Q stance, dr-n-butyl-tm dl-n-heptylate against Raillietina I umpmm 5- fl 2 1 Percesticilllls shows an efficacypf {14% at l00 mgJkg. body rected Wt. No. weight caps nle dosage, While its act1v1ty rises to 91% when given in the feed after only 44 mg./kg. body weight Di n buty1 fin dipmpionam 200 116 66 of the orug has been consumed. It seems as though the Dl-n-butyl-tin di-n-butyr- 100 11s 65 55 10 potency of the compound ncreases when the alimentary 200 80 66 83 method of administration is used. The following Table ijf fi '7i. }{;55.55%; 100 is 11 n1 XV illustrates additional instances wherein the comy -t p y 100 52 9 17 pounds develop a multiple or their activity when given a e. 4/4 200 12 8 67 5 111 feed as compared wrth capsule treatments.

Dl-n-butyl-tin dl-n-copryl- 100 38 68 bl XV ia tg ducal} CAPSULE AND FEED MEDICATION FOR RAILLIETINA 4/4 do 200 23 12 52 OESTIC'ILL US AND ASCARIDIA GALLI /8 Dl-n-butyi-tlu dilaurats 75 36 4 11 20 3/3- do 100 10 4 10 3/3- do. 150 22 12 55 Capsule Feed Etllcacy,Pereent aat a 22 1 Dose 'ly 63 9-- I 11 2. o 300 17 11 100 Cmnpmmd 35/5;- mtg-[kg- 4/3 Dl-henzyl-tln dlchloride 100 D 1 11 I, Wt Body Capsule Feed 4 o 200 10 g 60 2o Wt. 4/3- l-n-butyl-tln sulfate. 100 10 o 50 4/4- do 200 15 9 60 4/3- omplex di-n-butyI-flnox- 100 85 33 04 Railllzllno Ralllldtm lde-dichlorlde polymer. mflctllm umetllua 4/4 d0 200 10 10 100 Dl-n-butyl-tln cit-acetate 100 44 7a 100 4/1 Di-n-but mm sulfid 400 1 1 100 Dl-u-butyl-tln di-n-bu- 100 49 94 100 4 4. Dl-n-butyI-tlu phenoxlcle 100 15s 17 11 tyrate. 4 4 do 200 117 78 67 Dl-n-butyl-tln dl-n-val- 100 92 51 100 4/4 Dl-n-butyl-tin di-d-gluco- 200 42 38 91 grate.

note. Di-n-butyl-tln dl-n-hop- 100 49 44 01 4/3 Dl-n-hutyl-tln oxide 400 115 79 89 e. 3/3 Dl-n-butyl-tin dlbutoxlde 100 14 14 100 Dl-n-butyl-tln ul-undoc- 100 36 12 on 4/4 .do 200 34 34 100 ylen a. R 4/4 Dl-n-butyl-tin (hydroxy) 200 206 196 05 Dl-n-hutyl-ttnullaurate.. 100 46 93 75 mereapto-thlo-acetste Di-n-butyl-ttu maleete... 100 42 8o 97 polymer. Dl-allyl-tln d1laurate. 200 71 82 73 D1-n-hutyl-tin dl-(mereap- 91 82 Q0 D1-n-butyl-tln sulfatm-.. 100 87 fie tlde-lso-oetylaeetate). Dl-n-hutyl-tin arsonate 67 59 Aster/did Aamrldta .clo 63 65 I H yalli gall! Dl-n-butyl-tln di(mereep- 86 79 DI-n-butyl-tln (ll-acetate. 10D 76 56 100 tlde-ethyl-caprate). Dl'u-butyl-tln dl-n-bw 100 49 92 Di-n-bntyl-tin ethoxtde- 28 $3 tyrate.

ethyl-mercaptlde poly- Dl-n-butyl-th1exida 100 21 100 Inez.

Table No scientific explanation can be offered so far for this v a: 15 Irrf; 7-- FEED MIQMCQTEON F03 4 Grub omens-n. Bower/er, 1t may posslbly be connected Cale wn the size of the surface area of the carrier from which 1g Dos a D056; 3 ml fi compound evolves its anthelmintic action. Indica- Compound g -A mgJlrg. moved, trons go this dzrection are found in the fact that solid Imam Days e gr cent; materials other than reed, such as fullers earth and other clays, show the same potent1at1ng efieet. It is I obvious, however, that this mode of admlmstratlon great- 3;: gg 23 2g gg ly enhances the usefulness of our novel preparations as jj'j: 'iii. figi.'fga'f iflgi' 75/2 140 49 43 86 vermnugal 1 211166185. Whrle treatment with single medirl e. a cation units makes it necessary to capture individually %g%----- dg Oxide 5 88 the animals to insert the capsule or tablet into their throat, Ij: 5 fiii 5 3,551 50/1 44 34 50 the treatment w rth many of our compounds can be men tageo. W0 76 33 33 100 aged without tnese elfortsfoy simple feed medlcatron. 4 5H1 42 18 6 33 Furthermore the mcrease in anthelmlntrc potency pro bmymte' ides for greater economy, particularly 1n cases where 1 50/2 19 g6 23 fl toe same effect can he reached 111 feed with the third gf gggggg 50/1 or tourth part of the dose otherwise required by the 5/ 50/1 46 39 22 25 usual methods of capsule administration.

m. a 86 F0 3 N W Asalready mentioned, our new vermlfugal substances 7/ 28}; m 5 are lrkew1se adapted to be used on other animals. As 100/2 305 131 127 100 an illustrauon, an adult mongrel dog of an approximate 3i d 28/; 3 33 weight of 25 kg. was paras1t1zed with Taenia pisiformis 1J1? g b 3 and treated with 1.25 gm. of di-n-butyl-tin dilaurate cor- 1 vy lohlo 50/1 28 13 4. .50 W} wa 50/ (6 l 0 1 responding to 50 mg. per itg. bogy wglgltn The compound 0 i H was given In two capsu es. n t e o owing day nuif i morons proglottids and strobilae Without scolices were Dimnyl-ths malea 41 3 is recovered from the feces and no further discharge of such 0 1 7 1 5 54 M mmmlbethoxwemyb moh a} 21 62 seigmentis and wholeworms was observed thereafter un. mohyl-tin dibrot1 thef gagtwas sacrlticed. Necbropsyf revealed thie pres- V m e. m ence o u an msrgni cant num er 0 taeniae, in icating gg 'gggf 2M 35 14 a considerable activity of the compound. No toxic red@ 200 2 53s 21 17 11 ctions of any consequence were observed following Dl-lrdl-butyl-tln difiuo- 50/1 41 as 25 51 8 medication as evidenced by normal appetite and stools.

l 0. X Diaphutyl-tin arso- 50 2 7a 51 4O 78 9 mm l. A veterinary composition efiectlve 1n the control of Dl-n -huty-t u d /1 75 10 5 protozoal and helmmthie infections and in enhancing the g gfgg gj' fi meat producingcapacity and maturation of fowl and ntmmh um dt-uce- 1 onresue ted a lzoals, comprising an orally ingestihle h a small, eft ctive nontoxic of a tetravaient dibenzyltin compound selected from the group consisting of dibenzyl-tin oxide, dibenzyl-tin dichloride, dihenzyl-tin sulfide, dibenzyl-tin diacetate and dibenzyl-tin maleate, said compound being present in an amount not less than 0.0025% by weight of the composition.

2-; veterinary composition in accordance with claim 1, in which the orally ingestible vehicle is an animal feed ration.

3. A veterinary composition in accordance with claim 1', in which the orally ingestible vehicle is an aqueous drinking preparation.

l. A veterinary composition in accordance with claim 2, in which the active ingredient is dibenzyl-tin oxide.

A veterinary composition in accordance with claim 11 which the active ingredient is dibenzyl-tin sulfide. A veterinary composition in accordance with claim in which active ingredient is dibenzyl-tin diacetate. 7. A veterinary composition in accordance with claim which the active ingredient is dibenzyl-tin maleate. 8. A veterinary composition in accordance with claim is, in which the active ingredient is dibenzyl-tin dichloride. 9. A veterinary composition in accordance with claim in which the acitve ingredient is dibenzyl-tin oxide. 10. A veterinary composition in accordance with claim 5, in which the active ingredient is dibenzyl-tin sulfide.

11. A veterinary composition in accordance with claim 3, in which the active ingredient is di'oenzyl-tin diacetate.

12. A veterinary composition in accordance with claim 3, in which the active ingredient is dibenzyl-tin maleate.

13. A veterinary composition in accordance with claim 3, in which the active ingredient is dibenzyl-tin dichloride.

14. A nontoxic veterinary composition in dosage unit form effective in the control of helminthic infections in fowl and domesticated animals comprising a pharmacceutical carrier containing at least 3 mg. per dosage unit of a tetravalent dihenzyl-tin compound selected from the group consisting of dibenzyl-tin oxide, dibenzyl-tin di- 5 chloride, dibenzyl-tin sulfide, dibenzyl-tin diacetate and dibenzyl-tin maleate.

15. A nontoxic veterinary composition in accordance with claim 14, in which the active ingredient is dibenzyi tin oxide.

16. A nontoxic veterinary composition in accordance with claim 14, in which the active ingredient is dihenzyi= tin sulfide.

17. A nontoxic veterinary composition in accordance with claim 14, in which the active ingredient is dibenzyltin diacetate.

18. A nontoxic veterinary composition in accordanx with claim 14, in which the active ingredient is dibenzyh tin maleate.

19. A veterinary composition in accordance with claim 14, in which the active ingredient is dibenzyl-tin dichloride.

a eicrenees Eited in the file of this patent UNETEID STATES PATENTS OTHER REFERENCES Whitmore, flrganic Chemistry (1937), p. 220. Handbook of Chemistry and Physics, 28th Ed. (1944), pp. 1032 to 1035.

Guthrie, American Journal of Veterinary Research,

vol. 2, January 1941, pp. 108 to 116. 

1. A VETERINARY COMPOSITION EFFECTIVE IN THE CONTROL OF PROTOZOAL AND HELMINTHIC INFECTIONS AND IN ENHANCING THE MEAT PRODUCING CAPACITY AND MATURATION OF FOWL AND DOMESTICATED ANIMALS, COMPRISING AN ORALLY INGESTIBLE VEHICLE CONTAINING A SMALL, BUT EFFECTIVE NONTOXIC AMOUNT OF A TETRAVALENT DIBENZYL-TIN COMPOUND SELECTED FROM THE GROUP CONSISTING OF DIBENZYL-TIN XIDE, DIBENZYL-TIN DICHLORIDE, DIBENZYL-TIN SULFIDE, DIBENZYL-TIN DIACETATE AND DIBENZYL-TIN MALEATE. SAID COMPOUND BENG PRESENT IN AN AMOUNT NOT LESS THAN 0.0025% BY WEIGHT OF THE COMPOSITION. 